Single isomer methylphenidate and resolution process

ABSTRACT

Single isomer methylphenidate, selected from the d- and l-threo-enantiomers, has been obtained in purified form, to the extent of less than 2% by weight of a contaminant selected from resolving agent and ritalinic acid. This is achieved by resolution of a mixture of enantiomers using an O,O′-diaroyltartaric acid as resolving agent.

FIELD OF THE INVENTION

[0001] This invention relates to the resolution of threo methylphenidatevia crystallisation of diastereomeric salts, and to the especially pureenantiomers thus obtained.

BACKGROUND OF THE INVENTION

[0002] Methylphenidate is a therapeutic agent that is widely used in thetreatment of attention-deficient hyperactivity disorder. It is acontrolled substance.

[0003] Methylphenidate was first prepared as a mixture of the erythroand threo racemates. U.S. Pat. No. 2,957,880 discloses studies upon thetwo racemic mixtures, which revealed that the therapeutic activityresides in the threo diastereomer. It is now considered that it is thed-threo [or (R,R)] enantiomer that has the preferred therapeuticactivity. Uses of this enantiomer are disclosed in PCT/GB96/01688,PCT/GB96/01689 and PCT/GB96/01690, the contents of which areincorporated herein by reference.

[0004] The resolution of threo methylphenidate can be achieved using theexpensive resolving agent 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate,a process first reported by Patrick et al (The Journal of Pharmacologyand Experimental Therapeutics, 241:152-158 (1987)), and subsequentlyused by other workers in the field (e.g. Aoyama et al, Journal ofChromatography, 494:420 (1989)). This is perceived to be a moreefficient procedure than the method disclosed in U.S. Pat. No.2,957,880, wherein the corresponding amide of erythro methylphenidate(i.e. R-CONR₂ rather than R-CON₂Me) is resolved with tartaric acid priorto amide hydrolysis and equilibration at the benzylic centre, followedby esterification of the resultant threo-acid.

SUMMARY OF THE INVENTION

[0005] This invention is based upon the discovery that racemic threomethylphenidate can be resolved using inexpensive carboxylic acids,specifically O,O′-diaroyltartaric acids, with surprising efficiency. Inone embodiment of the present invention, either D- orL-O,O-di-toluoyltartaric acid forms diastereomeric salts withthreo-methylphenidate, and these salts are very readily separated.

[0006] An important consequence of this discovery is that the desiredenantiomer is obtained in greater chemical purity than by any priormethod. Thus, while the process of Patrick et al may give the desiredproduct contaminated with resolving agent, this contaminant can only beremoved by repeated extractions that cause hydrolysis of the ester,leaving ritalinic acid as a contaminant.

[0007] Needless to say, a product intended for administration to humansshould be as pure as possible. Surprisingly, the process of thisinvention gives the desired enantiomer in very high chemical andenantiomeric purity. In particular, the product is substantially free ofresolving agent and/or ritalinic acid (and/or the opposite enantiomer).This purity can be at least 98%, preferably at least 99%, morepreferably at least 99.5%, and most preferably at least 99.9%. Theproduct may be in free base form or as a pharmaceutically-acceptablesalt, e.g. the hydrochloride.

DESCRIPTION OF THE INVENTION

[0008] The process of this invention may be carried out under conditionsthat are generally known to those skilled in the art of classical saltresolution procedures. For example, a mixture of threo-methylphenidateand 1 molar equivalent of D-O,O-ditoluoyltartaric acid in an inertorganic solvent is heated and then allowed to cool; the resultantprecipitate is filtered, washed with an appropriate solvent and dried toafford directly a salt enriched in at least 97% eed-threo-methylphenidate, i.e containing less than 1.5% of the oppositeenantiomer. Enrichment to higher ee, e.g. at least 99%, can be simplyachieved, by reslurrying in fresh solvent and filtering. This is a greatimprovement on the literature method using 1,1′-binaphthyl-2,2′-diylhydrogen phosphate, described by Patrick et al, supra, in which thefirst crystallisation gave a salt corresponding to 85-90% ee material,and further recrystallisation of this material was necessary to raisethe ee to 95-97%. The latter level of optical purity is achieved in thepresent invention in one crystallisation, with an overall higher yield.The method of this invention is therefore more efficient and moreeconomical than the method described by Patrick et al.

[0009] Methylphenidate may initially be obtained as a salt of theresolving agent. This may be converted directly to the hydrochloridesalt, or any other pharmaceutically-acceptable salt, by a salt exchangeprocedure. It may be preferable to release the free base, by saltcracking. If desired, the free base can then be converted to a saltform. All these procedures are known to those skilled in the art.

[0010] Further advantages of the present invention are as follows:

[0011] (i) Salt cracking at pH 9-10 is by addition of aqueous sodiumhydroxide, whereas dilute aqueous sodium carbonate is needed for saltsof the more base-labile 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate;this renders the novel process more volume efficient.

[0012] (ii) Lower volume of aqueous medium in (i) means fewerextractions into organic solvent (TBME rather than diethyl ether) toisolate methylphenidate free base.

[0013] (iii) Chemical robustness of DTTA allows for clean and efficientrecovery.

[0014] Either isomer of methylphenidate can be easily obtained by thisprocedure, e.g. by simply using the D- or L-isomer of the diaroyltartaric acid derivative as required.

[0015] Single isomer methylphenidate according to this invention,especially pure d-threo-methylphenidate, can be used in therapy for thesame purposes as the racemate, e.g. in the treatment of ADHD ornarcolepsy. The compound can be formulated with any suitable carrier, inany suitable dosage, as will be apparent to one of ordinary skill in theart. Reference in this context may be made to any of the three PCTApplications identified above.

[0016] The following Example illustrates the invention.

EXAMPLE

[0017] Ditoluoyl-D-tartaric acid (5.033 g, 12.4 mmol) was suspended in asolution of 2% methanol in acetone (10 ml), and a solution ofthreo-methylphenidate (2.9 g, 12.4 mmol) in the same solvent (10 ml) wasadded. The solution was gently warmed to reflux whereupon all thereagents dissolved. The solution was immediately cooled and crystalsbegan to form. The solution was allowed to stand at 4° C. for 17 hoursand was then filtered. The crystals were washed with acetone (3×15 ml)and dried in vacuo to yield the ditoluoyl-D-tartrate salt of d-threomethylphenidate (3.516 g, 44.3% by weight; corresponding to 97% eed-threo methylphenidate, as determined by chiral HPLC after saltcracking). The mother liquors were dried in vacua to yield theditoluoyl-D-tartrate salt of l-threomethylphenidate as a solid, dry form(4.508 g, 50.5% yield, 88% ee).

[0018] The ditoluoyl-D-tartrate salt of d-threo-methylphenidate (3.486g), obtained as described above, was suspended in 2% methanol inacetone, and warmed to c. 40° C. and cooled. This did not dissolve thesolid which was stirred at room temperature for 24 hours. The suspensionwas filtered, the solid washed with acetone (10 ml) and dried in vacuo,to yield diastereomerically pure material (3.209 g, 92% recovery,corresponding to >99% ee d-threo-methylphenidate).

[0019] Repeating this protocol using isopropanol: methanol as thesolvent, gave the same salt, on initial crystallisation, enriched in atleast 98%. Reslurrying increased this.

[0020] For the purposes of comparison, USP gradedl-threo-methylphenidate hydrochloride (3.36 g) was dissolved in anaqueous solution of sodium carbonate (45 ml, 2% w/v), and the clearsolution was extracted with diethyl ether (3×50 ml). The combinedethereal layers were dried (MgSO₄), filtered, and evaporated to dryness.The resulting pale yellow oil together with(R)-(−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (3.36 g) weredissolved in a hot mixture of acetone/methanol (95:5). The solution wasgently stirred and cooled to 5° C. and maintained for 12 hours. Theresulting white crystals (2.98 g) were isolated by filtration andrecrystallised from acetone/methanol (98:2). This product was thentreated with a 2% aqueous solution of sodium carbonate and extractedwith diethyl ether (4×50 ml). The combined ethereal layers were dried(MgSO₄) and filtered. An excess saturated solution of hydrogen chloridein ether was then added and the resulting hydrochloride salt wasfiltered, rinsed with ether, and recrystallised from methanol/ether. Theresulting white crystalline product was analysed by HPLC and proton NMR:

[0021] % w/w l-threo: 3.7%

[0022] e.e.: 92.6%

[0023] ritalinic acid:t race amount but not quantified by HPLC or NMR

[0024] resolving agent: approximately 4% by NMR

[0025] It should be understood that the examples and embodimentsdescribed herein are for illustrative purposes only and that variousmodifications or changes in light thereof will be suggested to personsskilled in the art and are to be included within the spirit and purviewof this application and the scope of the appended claims.

We claim:
 1. A single isomer methylphenidate compound, selected from thegroup consisting of the d-threo- and l-threo-enantiomers, andpharmaceutically-acceptable salts thereof, wherein said compound is incombination with less than about 2% by weight of a contaminant selectedfrom the group consisting of resolving agents and ritalinic acid.
 2. Themethylphenidate compound, according to claim 1 , in combination withless than about 1% by weight of said contaminant.
 3. The methylphenidatecompound, according to claim 1 , in combination with less than about0.5% by weight of said contaminant.
 4. The methylphenidate compound,according to claim 1 , in combination with less than about 0.1% byweight of said contaminant.
 5. The methylphenidate compound, accordingto claim 1 , wherein said compound is in the free base form.
 6. Themethylphenidate compound, according to claim 1 , wherein said compoundis in the hydrochloride form.
 7. A single isomer methylphenidatecompound, selected from the group consisting of the d-threo- andl-threo-enantiomers, and pharmaceutically-acceptable salts thereof,wherein said compound is at least about 98% pure.
 8. The methylphenidatecompound, according to claim 7 , wherein said compound is at least about99% pure.
 9. The methylphenidate compound, according to claim 7 ,wherein said compound is at least about 99.5% pure.
 10. Themethylphenidate compound, according to claim 7 , wherein said compoundis at least about 99.9% pure.
 11. The methylphenidate compound,according to claim 7 , wherein said compound is in the free base form.12. The methylphenidate compound, according to claim 7 , wherein saidcompound is in the hydrochloride form.
 13. A pharmaceutical compositioncomprising a single isomer methylphenidate compound, selected from thegroup consisting of the d-threo-enantiomers, andpharmaceutically-acceptable salts thereof, and apharmaceutically-acceptable diluent or carrier.
 14. The pharmaceuticalcomposition, according to claim 13 , wherein said compound is incombination with less than about 2% by weight of a contaminant selectedfrom the group consisting of resolving agents and ritalinic acid. 15.The pharmaceutical composition, according to claim 13 , wherein saidcompound is at least about 98% pure.
 16. A method for treating a personhaving a condition susceptible to treatment with methylphenidatecomprising administering to the person an effective amount of a singleisomer methylphenidate compound selected from the group consisting ofd-threo-methylphenidate, and pharmaceutically-acceptable salts thereof.17. The method, according to claim 16 , wherein said methylphenidatecompound is in combination with less than about 2% by weight of acontaminant selected from the group consisting of resolving agents andritalinic acid.
 18. The method, according to claim 16 , wherein saidmethylphenidate compound is at least about 98% pure.
 19. The method,according to claim 16 , wherein the condition is selected from the groupconsisting of attention-deficient hyperactivity disorder and narcolepsy.20. A process for preparing substantially single enantiomer d- orl-threo-methylphenidate, which comprises resolution of a mixture ofenantiomers using an O,O′-diaroyltartaric acid as a resolving agent. 21.The process, according to claim 20 , which additionally comprises saltcracking using aqueous alkali metal hydroxide.